1. Field of the Invention
This invention relates to a lyophilized pharmaceutial composition of a neocarzinostatin derivative (hereinafter abbreviated as SMANCS) having styrene-maleic acid copolymeric residue.
2. Related Art Statement
SMANCS is a derivative of neocarzinostatin (hereinafter abbreviated as NCS), and is described in Japanese Patent Application Publication No. 42-21,752 being useful as as a proteinaceous anticancer substance. SMANCS is synthesized by bonding two molecules of a partially half-esterified styrene-maleic acid copolymer (hereinafter abbreviated as SMA) to one molecule of NCS through an acid amide (inkage and maybe expressed as (SMA)-(NCS)-(SMACS) as described in Japanese Patent laid open, No. 60-75,432 and No. 60-75,499. SMANCS is a cancerocidal substance exhibiting an excellent anticancer activity equal to that of NCS and having a reduced toxicity and an enhanced prolonged action as compared with NCS.
If it is intended to apply SMANCS to a human body as a parenteral injection, since SMANCS itself is a peptide, it is preferable that SMANCS is lyophilized and dissolved in an aqueous solvent in use.
However, while SMANCS is stable in a dark cold place (not higher than 5.degree. C., storage in a refrigerator), it is unstable at room, even in the lyophilized state, so that such an instability is a large obstacle when SMANCS is supplied as a drug. Therefore, a need exists it is demanded to develop a lyophilized pharmaceutical preparation of SMANCS having a high stability against heat and a good storability even at room temperature.
On the other hand, it is known that peptides having a biogenic property such as enzymes, hormones, lymphokine and the like are also unstable, not only in an aqueous solution in the liquid state but also in a lyophilized state, and are subject to a considerably loss of their biogenic properties. Therefore, the addition of a stabilizing agent is widely performed as a method of preventing the disappearance of the biogenic properties of peptides and enhancing the stability of the peptides.
For instance, D-glucose, D-galactose, D-xylose, D-glucuronic acid, trehalose, dextran, hydroxyethyl starch and the like are known as stabilizing agents in the storage, isolation, purification, lyophilization and the like of tumor necrosis factors (Japanese Patent laid open No. 59-59,625), and polysaccharides such as dextran and the like are known as a stabilizing agent for interferon (Japanese Patent laid open No. 60-59,000). As a result of various studies on stabilizing agents for interferon against heat, there are known, for example, glycerin, saccharose (Japanese Patent laid open No. 59-25,333), dextran, hydroxyethyl starch (Japanese Patent laid open No. 60-155,136), glycine, .alpha.-alanine and its salt and human serum albumin (Japanese Patent laid open No. 58-146,504), glutamic acid (Japanese Patent laid open No. 59-181,224), inorganic salts, particularly sodium chloride (Japanese Patent laid open No. 59-25,364) and the like. Further, mannitol is widely used as a stabilizing agent and an adjuvant in ordinary lyophilized preparations.
However, SMANCS is an NCS derivative obtained by bonding SMA as a polymer to NCS as a high molecular weight biogenic peptide as mentioned above, so that it is a very special cancerocidal substance possessing properties as a peptide and properties as a polymer. Therefore, the aforementioned well-known stabilizing agents for the biogenic peptide can not be applied to SMANCS as they are. In fact, the inventors have attempted the preparation of the lyophilized pharmaceutical composition of SMANCS by using glycine and serum albumin which are; well-known as stabilizing agents for peptides or mannitol, a well-known stabilizing agent and adjuvant for lyophilized preparations, but did not find an improvement in the stability thereof (see comparative Example 1-3 herein.